miR-886-3p Levels Are Elevated in Friedreich Ataxia

Mahishi, Lata; Hart, Ronald P.; Lynch, David R.; Ratan, Rajiv R.

doi:10.1523/jneurosci.0059-12.2012

Cited by 39 publications

(31 citation statements)

References 29 publications

(34 reference statements)

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“…The protein levels of the FXN gene are reduced and levels of miR-886-3p are increased in patient samples suggesting that this small RNA is involved in the pathology of FRDA. Treatment with an antimiR targeting miR-886-3p led to the increase of FXN expression demonstrating that this miRNA is a promising therapeutic target for FRDA [129]. The most advanced miRNA based therapy is Miravirsen which is currently in late-stage clinical trials for the treatment of chronic hepatitis C virus (HCV) infection.…”

Section: Microrna Therapymentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post-transcriptionally, typically recognising binding sites in the 3′ untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases.

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Section: Microrna Therapymentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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“…miR-124 is among the miRNAs the most enriched in the central nervous system, where it plays a crucial role in neurogenesis and neuronal function (reviewed by [28]). Recently, miR-124 was found as overexpressed in FRDA patient cells [17]. As such, the specific regulation of FRDA-3′-UTR by miR-124 likely plays a role in the neuropathology of Friedreich ataxia.…”

Section: Discussionmentioning

confidence: 98%

“…In FRDA, involvement of miRNAs has been shown to contribute to the cardiac phenotype through the differential targeting of AGTR1 by miR-155 [16]. More recently, a small non-coding RNA, miR-886-3p, which is no longer considered as a miRNA (miRBase, release 16), was found elevated in peripheral blood of FRDA patients and was shown to influence frataxin transcription [17]. Through studying the FXN 3′UTR, we sought whether FRDA patients could harbor any specific post-transcriptional regulation of frataxin related to miRNA.…”

Section: Introductionmentioning

confidence: 99%

Genetic Variations Creating MicroRNA Target Sites in the FXN 3′-UTR Affect Frataxin Expression in Friedreich Ataxia

et al. 2013

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Friedreich’s ataxia (FRDA) is a severe neurodegenerative disease caused by GAA repeat expansion within the first intron of the frataxin gene. It has been suggested that the repeat is responsible for the disease severity due to impaired transcription thereby reducing expression of the protein. However, genotype-phenotype correlation is imperfect, and the influence of other gene regions of the frataxin gene is unknown. We hypothesized that FRDA patients may harbor specific regulatory variants in the 3′-UTR. We sequenced the 3′-UTR region of the frataxin gene in a cohort of 57 FRDA individuals and 58 controls. Seven single nucleotide polymorphisms (SNPs) out of 19 were polymorphic in our case-control sample. These SNPs defined several haplotypes with one reaching 89% of homozygosity in patients versus 24% in controls. In another cohort of 47 FRDA Reunionese patients, 94% patients were found to be homozygous for this haplotype. We found that this FRDA 3′-UTR conferred a 1.2-fold decrease in the expression of a reporter gene versus the alternative haplotype configuration. We established that differential targeting by miRNA could account for this functional variability. We specifically demonstrated the involvement of miR-124 (i.e hsa-mir-124-3p) in the down-regulation of FRDA-3′-UTR. Our results suggest for the first time that post-transcriptional regulation of frataxin occurs through the 3′-UTR and involves miRNA targeting. We propose that the involvement of miRNAs in a FRDA-specific regulation of frataxin may provide a rationale to increase residual levels of frataxin through miRNA-inhibitory molecules.

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“…Another recent study demonstrated that levels of an miRNA, miR-886-3p, are elevated in cell lines and blood samples derived from patients with Friedreich ataxia and that this miRNA plays a role in silencing FXN expression. 21 In addition, epigenetic mechanisms regulate genes and pathways involved in disease processes arising from environmental exposures or genetic and environmental interactions. One study focusing on chronic pain syndromes caused by peripheral nervous system injuries demonstrated that C-fiber dysfunction is mediated by decreased levels of sodium channel, voltage-gated, type X, alpha subunit and opioid receptor, mu 1 expression in the dorsal root ganglion and that REST is responsible for the down-regulation of these genes in response to injury.…”

Section: Paradigms Linking Epigenetics With Neurological Disease Procmentioning

confidence: 99%

Understanding Neurological Disease Mechanisms in the Era of Epigenetics

Qureshi

Mehler²

2013

JAMA Neurol

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he burgeoning field of epigenetics is making a significant impact on our understanding of brain evolution, development, and function. In fact, it is now clear that epigenetic mechanisms promote seminal neurobiological processes, ranging from neural stem cell maintenance and differentiation to learning and memory. At the molecular level, epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues, including the deployment of cell type-specific gene networks and those underlying synaptic plasticity. Pharmacological and genetic manipulation of epigenetic factors can, in turn, induce remarkable changes in neural cell identity and cognitive and behavioral phenotypes. Not surprisingly, it is also becoming apparent that epigenetics is intimately involved in neurological disease pathogenesis. Herein, we highlight emerging paradigms for linking epigenetic machinery and processes with neurological disease states, including how (1) mutations in genes encoding epigenetic factors cause disease, (2) genetic variation in genes encoding epigenetic factors modify disease risk, (3) abnormalities in epigenetic factor expression, localization, or function are involved in disease pathophysiology, (4) epigenetic mechanisms regulate diseaseassociated genomic loci, gene products, and cellular pathways, and (5) differential epigenetic profiles are present in patient-derived central and peripheral tissues.

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miR-886-3p Levels Are Elevated in Friedreich Ataxia

Cited by 39 publications

References 29 publications

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

Genetic Variations Creating MicroRNA Target Sites in the FXN 3′-UTR Affect Frataxin Expression in Friedreich Ataxia

Understanding Neurological Disease Mechanisms in the Era of Epigenetics

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